1. {{Autism spectrum disorder}}. {Nurs Stand};2015 (May 20);29(38):19.
Essential facts Autism spectrum disorder (ASD) is a lifelong developmental condition affecting social interaction, communication and behaviour. Symptoms vary from person to person and range from mild to severe. Since the 1970s the reported prevalence of ASD has risen substantially, from less than 0.05% of the population to at least 1%. According to the National Autistic Society, about four times as many boys as girls are diagnosed.
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2. Agha HM, El-Saiedi SA, Shaltout MF, Hamza HS, Nassar HH, Abdel-Aziz DM, Tantawy AE. {{Incomplete RV Remodeling After Transcatheter ASD Closure in Pediatric Age}}. {Pediatr Cardiol};2015 (May 17)
Published data showing the intermediate effect of transcatheter device closure of atrial septal defect (ASD) in the pediatric age-group are scarce. The objective of the study was to assess the effects of transcatheter ASD closure on right and left ventricular functions by tissue Doppler imaging (TDI). The study included 37 consecutive patients diagnosed as ASD secundum by transthoracic echocardiography and TEE and referred for transcatheter closure at Cairo University Specialized Pediatric Hospital, Egypt, from October 2010 to July 2013. Thirty-seven age- and sex-matched controls were selected. TDI was obtained using the pulsed Doppler mode, interrogating the right cardiac border (the tricuspid annulus) and lateral mitral annulus, and myocardial performance index (MPI) was calculated at 1-, 3-, 6- and 12-month post-device closure. Transcatheter closure of ASD and echocardiographic examinations were successfully performed in all patients. There were no significant differences between two groups as regards the age, gender, weight or BSA. TDI showed that patients with ASD had significantly prolonged isovolumetric contraction, relaxation time and MPI compared with control group. Decreased tissue Doppler velocities of RV and LV began at one-month post-closure compared with the controls. Improvement in RVMPI and LVMPI began at 1-month post-closure, but they are still prolonged till 1 year. Reverse remodeling of right and left ventricles began 1 month after transcatheter ASD closure, but did not completely normalize even after 1 year of follow-up by tissue Doppler imaging.
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3. Al-Zaid FS, Alhader AA, Al-Ayadhi LY. {{The second to fourth digit ratio (2D:4D) in Saudi boys with autism: A potential screening tool}}. {Early Hum Dev};2015 (May 13);91(7):413-415.
BACKGROUND: Autism is a neurodevelopment disorder with a strikingly higher prevalence in boys than girls. There are many theories regarding this gender bias, and prenatal exposure to high levels of fetal testosterone (FT) may be a predisposing factor. The second to fourth digit ratio (2D:4D) is the only indirect measure that reflects this association postnatally. Thus, this study measured the lengths of the index finger (2D) and the ring finger (4D) and calculated the 2D:4D ratio. Subsequently, this ratio was used to indirectly determine the potential prenatal exposure to high levels of FT in autistic children. METHODS: This case-control study was conducted with 60 male children with 31 individuals having classic-onset autism and 29 individuals serving as age-matched, healthy controls. The lengths of both the index (2D) and the ring (4D) fingers of the right hand of both autism and control groups were obtained using a scanner and the 2D:4D ratio was calculated. RESULTS: The 2D:4D ratio in the current study was significantly lower in boys with autism compared to the controls (p</=0.001). CONCLUSIONS: This study demonstrates a significantly lower 2D:4D ratio in Saudi boys with autism, which indirectly suggests that these boys were exposed to high levels of prenatal FT. Accordingly, prenatal exposure to high levels of FT is a risk factor for the development of autism, and the postnatal measurement of the 2D:4D ratio could be a potential screening tool.
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4. Bakos J, Bacova Z, Grant SG, Castejon AM, Ostatnikova D. {{Are Molecules Involved in Neuritogenesis and Axon Guidance Related to Autism Pathogenesis?}}. {Neuromolecular Med};2015 (May 20)
Autism spectrum disorder is a heterogeneous disease, and numerous alterations of gene expression come into play to attempt to explain potential molecular and pathophysiological causes. Abnormalities of brain development and connectivity associated with alterations in cytoskeletal rearrangement, neuritogenesis and elongation of axons and dendrites might represent or contribute to the structural basis of autism pathology. Slit/Robo signaling regulates cytoskeletal remodeling related to axonal and dendritic branching. Components of its signaling pathway (ABL and Cdc42) are suspected to be molecular bases of alterations of normal development. The present review describes the most important mechanisms underlying neuritogenesis, axon pathfinding and the role of GTPases in neurite outgrowth, with special emphasis on alterations associated with autism spectrum disorders. On the basis of analysis of publicly available microarray data, potential biomarkers of autism are discussed.
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5. Chen JL, Sung C, Pi S. {{Vocational Rehabilitation Service Patterns and Outcomes for Individuals with Autism of Different Ages}}. {J Autism Dev Disord};2015 (May 16)
Young adults with autism spectrum disorders (ASD) often experience employment difficulties. Using Rehabilitation Service Administration data (RSA-911), this study investigated the service patterns and factors related to the employment outcomes of individuals with ASD in different age groups. Hierarchical logistic regression analyses were conducted to examine the effects of demographic and vocational rehabilitation (VR) service variables on employment outcomes in each age group. The results show that transition youth made up the largest portion of VR service users among the ASD population, yet they have the worst employment outcomes across all age groups. Factors that are significantly associated with increased odds for employment in each age group were identified. Implications from systemic, practical, and research perspectives are also provided.
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6. Cochran L, Moss J, Nelson L, Oliver C. {{Contrasting age related changes in autism spectrum disorder phenomenology in Cornelia de Lange, Fragile X, and Cri du Chat syndromes: Results from a 2.5 year follow-up}}. {Am J Med Genet C Semin Med Genet};2015 (May 18)
Little is known about the way in which the characteristics of autism spectrum disorder (ASD) develop and manifest across the age span in individuals with genetic syndromes. In this study we present findings from a two and a half year follow-up of the characteristics associated with ASD in three syndromes: Cornelia de Lange (CdLS), Fragile X (FXS), and Cri du Chat (CdCS). Parents and carers of 251 individuals (CdLS = 67, CdCS = 42, and FXS = 142) completed the Social Communication Questionnaire (SCQ) at Time 1 (T1) and again two and a half years later (T2). The FXS and CdLS groups were more likely to meet the cut-offs for both autism and ASD and show greater severity of ASD related behaviors, at both T1 and T2, compared to the CdCS group. Older individuals (>15yrs) with CdLS were more likely to meet the cut off for ASD than younger individuals (</= 15yrs) with the syndrome and more likely to show greater severity of social impairments. In FXS repetitive behaviors were found to become less prominent with age and in CdCS social impairments were reported to be more severe with age. There were no significant changes between T1 and T2 in the severity of ASD characteristics in the CdCS and CdLS groups. The FXS group showed significantly fewer repetitive behaviors and less severe impairments in social interaction over this time frame. The findings suggest that while there may be similarities in overall severity and presentation of ASD characteristics in CdLS and FXS, these characteristics have divergent patterns of development within these groups. (c) 2015 Wiley Periodicals, Inc.
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7. Cronk JC, Derecki NC, Litvak V, Kipnis J. {{Unexpected cellular players in Rett syndrome pathology}}. {Neurobiol Dis};2015 (May 14)
Rett syndrome is a devastating neurodevelopmental disorder, primarily caused by mutations of methyl CpG-binding protein 2 (MeCP2). Although the genetic cause of disease was identified over a decade ago, a significant gap still remains in both our clinical and scientific understanding of its pathogenesis. Neurons are known to be primary players in pathology, with their dysfunction being the key in Rett syndrome. While studies in mice have demonstrated a clear causative – and potential therapeutic – role for neurons in Rett syndrome, recent work has suggested that other tissues also contribute significantly to progression of the disease. Indeed, Rett syndrome is known to present with several common peripheral pathologies, such as osteopenia, scoliosis, gastrointestinal problems including nutritional defects, and general growth deficit. Mouse models assessing the potential role of non-neuronal cell types have confirmed both roles in disease and potential therapeutic targets. A new picture is emerging in which neurons both initiate and drive pathology, while dysfunction of other cell types and peripheral tissues exacerbate disease, possibly amplifying further neurologic problems, and ultimately result in a positive feedback loop of progressively worsening symptoms. Here, we review what is known about neuronal and non-neuronal cell types, and discuss how this new, integrative understanding of the disease may allow for additional clinical and scientific pathways for treating and understanding Rett syndrome.
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8. Davis PE, Peters JM, Krueger DA, Sahin M. {{Tuberous Sclerosis: A New Frontier in Targeted Treatment of Autism}}. {Neurotherapeutics};2015 (May 19)
Tuberous sclerosis complex (TSC) is a genetic disorder with a high prevalence of autism spectrum disorder (ASD). Tremendous progress in understanding the pathogenesis of TSC has been made in recent years, along with initial trials of medical treatment aimed specifically at the underlying mechanism of the disorder. At the cellular level, loss of TSC1 or TSC2 results in upregulation of the mechanistic target of rapamycin (mTOR) pathway. At the circuitry level, TSC and mTOR play crucial roles in axonal, dendritic, and synaptic development and function. In this review, we discuss the molecular mechanism underlying TSC, and how this disease results in aberrant neural connectivity at multiple levels in the central nervous system, leading to ASD symptoms. We then review recent advances in mechanism-based treatments of TSC, and the promise that these treatments provide for future mechanism-based treatment of ASD. Because of these recent advances, TSC represents an ideal model for how to make progress in understanding and treating the mechanisms that underlie ASD in general.
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9. Gentile S. {{Prenatal antidepressant exposure and the risk of autism spectrum disorders in children. Are we looking at the fall of Gods?}}. {J Affect Disord};2015 (May 6);182:132-137.
Recent information suggests that antenatal exposure to psychotropics may impair child neurodevelopment. Thus, aim of this review is to examine systematically available literature investigating potential associations between prenatal use of selective serotonin reuptake inhibitors (SSRIs) and the risk of autism spectrum disorders (ASDs). METHODS: Medical literature published in English since 1988 identified using MEDLINE/PubMed, EMBASE, SCOPUS, and The Cochrane Library. Search terms: antidepressants, autism (spectrum disorders), childhood, children, neurodevelopment, pregnancy, SSRIs. Searches were updated until March 5, 2015. RESULTS: Six out of eight reviewed articles confirm an association between antenatal SSRI exposure and an increased risk of ASDs in children. However, the epidemiologic evidence on the link between prenatal SSRI exposure and ASD risk must still be cautiously interpreted, because of potential biases of analyzed research. LIMITATIONS: Main limitations of reviewed studies include: lack of directly validated clinical evaluation, impossibility to identify women who really took the prescribed medications during pregnancy, no assessment of severity and course of symptoms in relation to the pregnancy, lack of information about unhealthy prenatal lifestyle behaviors. CONCLUSIONS: Despite such limitations, available data show that some signal exists suggesting that antenatal exposure to SSRIs may increase the risk of ASDs. Thus, there is an urgent need for further, large, well-designed research finalized to definitively assess the existence and the magnitude of this severe risk, thus confirming or denying that we are truly looking at « the fall of Gods », since for many years SSRIs have been considered the first-choice agents for treating antenatal depression (Gentile, 2014; Gentile, 2011a; Gentile, 2005).
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10. Goldin RL, Matson JL. {{Premature birth as a risk factor for autism spectrum disorder: Brief report}}. {Dev Neurorehabil};2015 (May 20):1-4.
OBJECTIVE: Autism spectrum disorder (ASD) is common, life-long in nature, and can be very debilitating. Thus, an intensive search is on to identify the potential risk factors for the disorder. Premature birth has been identified as one potential factor that could influence potential symptoms of ASD. METHOD: The sample for this study consisted of 1655 at risk children for developmental delays who were 17-37 months of age. Participants were divided into those diagnosed with ASD (n = 916) and children with atypical development only (n = 739). RESULTS: Premature births were almost twice as common for the atypical development group versus the ASD group. CONCLUSIONS: Implications of these data are discussed.
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11. Gross C, Hoffmann A, Bassell GJ, Berry-Kravis EM. {{Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back}}. {Neurotherapeutics};2015 (May 19)
Fragile X syndrome (FXS), an inherited intellectual disability often associated with autism, is caused by the loss of expression of the fragile X mental retardation protein. Tremendous progress in basic, preclinical, and translational clinical research has elucidated a variety of molecular-, cellular-, and system-level defects in FXS. This has led to the development of several promising therapeutic strategies, some of which have been tested in larger-scale controlled clinical trials. Here, we will summarize recent advances in understanding molecular functions of fragile X mental retardation protein beyond the well-known role as an mRNA-binding protein, and will describe current developments and emerging limitations in the use of the FXS mouse model as a preclinical tool to identify therapeutic targets. We will review the results of recent clinical trials conducted in FXS that were based on some of the preclinical findings, and discuss how the observed outcomes and obstacles will inform future therapy development in FXS and other autism spectrum disorders.
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12. Herguner A, Herguner S. {{Association between age at menarche and autistic traits in Turkish university students}}. {Am J Hum Biol};2015 (May 20)
OBJECTIVES: The androgen theory of autism suggests that masculinizing effect of fetal androgens may play a role in the expression of autism. Recent evidence showed that excessive prenatal androgen exposure might delay age at menarche (AAM). The aim of this study was to investigate the relation between autistic traits and AAM in a sample of nonclinical female university students. METHODS: Autistic traits were measured using the Autism Spectrum Quotient (AQ), and AAM was questioned by retrospective self-reports. The AQ was completed by 436 female university students. RESULTS: There were significant positive correlations between AAM and AQ total and subscales measuring Social Skills, Communication, and Imagination. Subjects with above average autistic traits reported later AAM than subjects with below average autistic traits. CONCLUSION: These findings suggest that there may be a common developmental mechanism between delayed menarche and autistic traits, possibly through elevated levels of prenatal androgens. Am. J. Hum. Biol., 2015. (c) 2015 Wiley Periodicals, Inc.
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13. Johnson N, Van Hecke A. {{Increasing Autism Awareness in Inner-City Churches: A Brief Report}}. {J Pediatr Nurs};2015 (May 15)
Autism diagnosis rates trail significantly in the African American community. This pre-test post-test pilot study evaluated an African American inner-city church health ambassadors (HAs) autism spectrum disorder (ASD) awareness training session. The participants included 12 HAs who attended the 1hour training session organized by the National Baptist Convention, USA, Inc. Results of surveys showed higher mean scores post training for (1) HA attitudes about the potential for children to improve with applied behavior analysis therapy; (2) HA self-efficacy for having information about ASD screening materials; (3) strategies HAs could use to help parents/caregivers of children with developmental delays and challenging behaviors; (4) HA confidence in referrals for children with signs of ASD; (5) HA knowledge of measures to take to maximize a child’s chance of receiving an ASD evaluation; and (6) HA comfort for talking to parents about children with challenging behaviors. Several of these effects were maintained 3months later. Findings underscore the usefulness of the intervention for increasing the dissemination of knowledge about ASD and the opportunity to positively affect ASD screening, early intervention, and policy standards applicable to this vulnerable population.
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14. Lee EJ, Lee H, Huang TN, Chung C, Shin W, Kim K, Koh JY, Hsueh YP, Kim E. {{Trans-synaptic zinc mobilization improves social interaction in two mouse models of autism through NMDAR activation}}. {Nat Commun};2015;6:7168.
Genetic aspects of autism spectrum disorders (ASDs) have recently been extensively explored, but environmental influences that affect ASDs have received considerably less attention. Zinc (Zn) is a nutritional factor implicated in ASDs, but evidence for a strong association and linking mechanism is largely lacking. Here we report that trans-synaptic Zn mobilization rapidly rescues social interaction in two independent mouse models of ASD. In mice lacking Shank2, an excitatory postsynaptic scaffolding protein, postsynaptic Zn elevation induced by clioquinol (a Zn chelator and ionophore) improves social interaction. Postsynaptic Zn is mainly derived from presynaptic pools and activates NMDA receptors (NMDARs) through postsynaptic activation of the tyrosine kinase Src. Clioquinol also improves social interaction in mice haploinsufficient for the transcription factor Tbr1, which accompanies NMDAR activation in the amygdala. These results suggest that trans-synaptic Zn mobilization induced by clioquinol rescues social deficits in mouse models of ASD through postsynaptic Src and NMDAR activation.
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15. Mahajnah M, Sharkia R, Shalabe H, Terkel-Dawer R, Akawi A, Zelnik N. {{Clinical characteristics of autism spectrum disorder in Israel: impact of ethnic and social diversities}}. {Biomed Res Int};2015;2015:962093.
Despite the increased global prevalence and recognition of autistic spectrum disorder (ASD), it is still scarcely reported in the Arab world. Though Israel has a higher prevalence of ASD, a previous national survey of patients diagnosed between 1972 and 2004, demonstrated that 98% of them were of Jewish ancestry. The disproportional low number of Arab children with ASD in Israel is unclear but may reflect lower awareness and cultural bias. In the present study we collected clinical and demographic characteristics of 200 children with ASD from Arab and Jewish sectors in Israel that were evaluated in two child development centers. We compared the incidence and the medical comorbidity of autism between these two ethnics groups. The medical and psychiatric comorbidity profile in these children was similar to the worldwide published studies. In the present study the prevalence of autism in the Arab sector in Israel was similar to that of the Jewish sector. The Arab patients presented with more severe autistic manifestations and higher incidence of mental retardation, familial members with autism, and consanguinity (P < 0.05), while in the Jewish sector milder forms (such as Asperger syndrome and PDD-NOS) were more frequent. This discrepancy might be explained by both genetic and cultural factors.
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16. Mandic-Maravic V, Pejovic-Milovancevic M, Mitkovic-Voncina M, Kostic M, Aleksic-Hil O, Radosavljev-Kircanski J, Mincic T, Lecic-Tosevski D. {{Sex differences in autism spectrum disorders: does sex moderate the pathway from clinical symptoms to adaptive behavior?}}. {Sci Rep};2015;5:10418.
We explored sex differences in diagnostic categories, clinical symptoms and adaptive behavior of persons with autism spectrum disorders, as well as sex-specific correlations of clinical and adaptive caracteristics. The study involved 108 patients (83 males, 6.73 +/- 4.33 years old) diagnosed with autism spectrum disorders (ASD). Assessment included ADI-R and Vineland Adaptive Behavior Scale II. Males were more often diagnosed with typical autism. There were no sex differences in the autistic symptoms, while females showed better functioning in Daily living skills, without reaching statistically significant difference (p = 0.062). We have found different associations of autistic symptoms with different aspects of adaptive behavior in males and females. Social reciprocity in females correlated with social domain of adaptive behavior, in a positive direction. Our findings have shown that although there are no sex differences in autistic symptoms, females tend to be somewhat more functional, and are also less frequently diagnosed with typical autism. Our results have also shown that sex might moderate the way clinical symptoms are expressed in adaptive behavior. Social reciprocity might be the core feature regarding sex differences in ASD. Our findings might have diagnostic and therapeutical implications, pointing out to the need for individualized, sex-specific treatment in this group of disorders.
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17. Olde Loohuis NF, Kole K, Glennon JC, Karel P, Van der Borg G, Van Gemert Y, Van den Bosch D, Meinhardt J, Kos A, Shahabipour F, Tiesinga P, Van Bokhoven H, Martens GJ, Kaplan BB, Homberg JR, Aschrafi A. {{Elevated microRNA-181c and microRNA-30d levels in the enlarged amygdala of the valproic acid rat model of autism}}. {Neurobiol Dis};2015 (May 16)
Autism spectrum disorders are severe neurodevelopmental disorders, marked by impairments in reciprocal social interaction, delays in early language and communication, and the presence of restrictive, repetitive and stereotyped behaviors. Accumulating evidence suggests that dysfunction of the amygdala may be partially responsible for the impairment of social behavior that is a hallmark feature of ASD. Our studies suggest that a valproic acid (VPA) rat model of ASD exhibits an enlargement of the amygdala as compared to controls rats, similar to that observed in adolescent ASD individuals. Since recent research suggests that altered neuronal development and morphology, as seen in ASD, may result from a common post-transcriptional process that is under tight regulation by microRNAs (miRs), we examined genome-wide transcriptomics expression in the amygdala of rats prenatally exposed to VPA, and detected elevated miR-181c and miR-30d expression levels as well as dysregulated expression of their cognate mRNA targets encoding proteins involved in neuronal system development. Furthermore, selective suppression of miR-181c function attenuates neurite outgrowth and branching, and results in reduced synaptic density in primary amygdalar neurons in vitro. Collectively, these results implicate the small non-coding miR-181c in neuronal morphology, and provide a framework of understanding how dysregulation of a neurodevelopmentally relevant miR in the amygdala may contribute to the pathophysiology of ASD.
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18. O’Neill S. {{The countertransference impact of autistic defence in an otherwise neurotic patient}}. {Int J Psychoanal};2015 (May 19)
This paper investigates the question of why, in the psychoanalytic psychotherapy of a patient with encapsulated autistic pathology, the steady maintenance of a therapeutically neutral stance can be especially difficult. Transference and countertransference vicissitudes are examined. The author notices that the patient’s intolerance of ‘opposites’ (cf. Tustin, 1986), combined with extreme antipathy to having that intolerance noticed, can elicit corresponding, and potentially destabilizing, countertransference reactions. These reactions comprise an unstable tension between co-existing pressures towards fusion with, or expulsion of, the patient, their co-existence under further pressure to remain unnoticed. Until perceived, this state of affairs risks collusion with the pressure either to merge with or to expel the patient, and compromises the capacity to notice the detail of the transference process and even to notice co-existent positive and negative transference images. Detailed clinical illustration is given, including a session where it was difficult to notice the patient’s experience of a couple as a combined object. The author finds these observations of bipolar countertransference tensions illuminated by Green’s concepts of positive and negative narcissism and of the disobjectalizing function, and specifically accounted for by Ribas’s theory of autism as radical drive defusion.
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19. Pierce K, Marinero S, Hazin R, McKenna B, Barnes CC, Malige A. {{Eye Tracking Reveals Abnormal Visual Preference for Geometric Images as an Early Biomarker of an Autism Spectrum Disorder Subtype Associated with Increased Symptom Severity}}. {Biol Psychiatry};2015 (Apr 11)
BACKGROUND: Clinically and biologically, autism spectrum disorder (ASD) is heterogeneous. Unusual patterns of visual preference as indexed by eye tracking are hallmarks; however, whether they can be used to define an early biomarker of ASD as a whole or leveraged to define a subtype is unclear. To begin to examine this issue, large cohorts are required. METHODS: A sample of 334 toddlers from six distinct groups (115 toddlers with ASD, 20 toddlers with ASD features, 57 toddlers with developmental delay, 53 toddlers with other conditions [e.g., premature birth, prenatal drug exposure], 64 toddlers with typical development, and 25 unaffected toddlers with siblings with ASD) was studied. Toddlers watched a movie containing geometric and social images. Fixation duration and number of saccades within each area of interest and validation statistics for this independent sample were computed. Next, to maximize power, data from our previous study (n = 110) were added for a total of 444 subjects. A subset of toddlers repeated the eye-tracking procedure. RESULTS: As in the original study, a subset of toddlers with ASD fixated on geometric images >69% of the time. Using this cutoff, sensitivity for ASD was 21%, specificity was 98%, and positive predictive value was 86%. Toddlers with ASD who strongly preferred geometric images had 1) worse cognitive, language, and social skills relative to toddlers with ASD who strongly preferred social images and 2) fewer saccades when viewing geometric images. Unaffected siblings of ASD probands did not show evidence of heightened preference for geometric images. Test-retest reliability was good. Examination of age effects suggested that this test may not be appropriate with children >4 years old. CONCLUSIONS: Enhanced visual preference for geometric repetition may be an early developmental biomarker of an ASD subtype with more severe symptoms.
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20. Rice LJ, Gray KM, Howlin P, Taffe J, Tonge BJ, Einfeld SL. {{The developmental trajectory of disruptive behavior in Down syndrome, fragile X syndrome, Prader-Willi syndrome and Williams syndrome}}. {Am J Med Genet C Semin Med Genet};2015 (May 15)
The aim of this study was to investigate the developmental trajectories of verbal aggression, physical aggression, and temper tantrums in four genetic syndrome groups. Participants were part of the Australian Child to Adult Development Study (ACAD), which collected information from a cohort of individuals with an intellectual disability at five time points over 18 years. Data were examined from a total of 248 people with one of the four following syndromes: Down syndrome, Fragile X syndrome, Prader-Willi syndrome, or Williams syndrome. Changes in behaviors were measured using validated items from the Developmental Behavior Checklist (DBC). The results indicate that, while verbal aggression shows no evidence of diminishing with age, physical aggression, and temper tantrums decline with age before 19 years for people with Down syndrome, Fragile X syndrome, and William syndrome; and after 19 years for people with Prader-Willi syndrome. These findings offer a somewhat more optimistic outlook for people with an intellectual disability than has previously been suggested. Research is needed to investigate the mechanisms predisposing people with PWS to persistence of temper tantrums and physical aggression into adulthood. (c) 2015 Wiley Periodicals, Inc.
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21. Rueda JR, Guillen V, Ballesteros J, Tejada MI, Sola I. {{L-acetylcarnitine for treating fragile X syndrome}}. {Cochrane Database Syst Rev};2015 (May 19);5:CD010012.
BACKGROUND: People with fragile X syndrome (FXS) have an intellectual dysfunction that can range from very mild to severe. Symptoms can include speech and language delays and behavioural difficulties such as aggression or self injurious behaviours, emotional lability, and anxiety-related problems (for example obsessive-compulsive symptoms and perseverative behaviours). In some cases, affected people may have an additional diagnosis of attention deficit hyperactivity disorder or an autism spectrum disorder. OBJECTIVES: To review the efficacy and safety of L-acetylcarnitine in improving the psychological, intellectual, and social performance of people with FXS. SEARCH METHODS: In May 2015 we searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, PsycINFO, Web of Science, and two other databases. We also searched three trials registers, four theses databases, and the reference lists of relevant studies and reviews. SELECTION CRITERIA: Randomised controlled trials (RCTs) that assessed the efficacy of L-acetylcarnitine, at any dose, in people of any age diagnosed with FXS compared with placebo. DATA COLLECTION AND ANALYSIS: For each trial, two review authors independently extracted data on the children included and interventions compared, and assessed the risk of bias of the studies across the following domains: randomisation sequence generation, allocation concealment, blinding (of participants, personnel, and outcome assessors), incomplete outcome data, selective outcome reporting, and other potential sources of bias. MAIN RESULTS: We found only two RCTs that compared oral L-acetylcarnitine (LAC) with oral placebo in children with FXS. The studies included a total of 83 participants, all of them male, who were treated and followed for one year. The age of participants at the start of treatment ranged from 6 to 13 years, with a mean age of 9 years. Neither study provided information on randomisation, allocation concealment procedures, or blinding of outcome assessment, and we received no responses from the authors we emailed for clarification. We therefore rated studies as being at unclear risk of bias on these domains. We judged both studies to be at low risk of bias for blinding of participants and personnel, incomplete outcome data, and selective reporting, but to be at high risk of other bias, as at least one study was funded by a drug company, and in both studies people working for the company were part of the research team.We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to rate the quality of the available evidence. Overall, the quality of the evidence was low due to the imprecision of results and high risk of other bias.Regarding the primary outcome of psychological and learning capabilities, both studies assessed the effect of interventions on children’s verbal and non-verbal intellectual functioning using the Wechsler Intelligence Scale for Children – Revised. The authors did not provide detailed data on those results but said that they found no important differences between treatment and placebo.Both studies evaluated the impact of the treatment on hyperactive behaviour using the Conners’ Abbreviated Parent-Teacher Questionnaire. In one study, teachers’ assessments of the children found no clear evidence of a difference (mean difference (MD) 0.50, 95% confidence interval (CI) -5.08 to 6.08, n = 51; low-quality evidence). The other study stated that there were no differences between treated and untreated participants, but did not provide detailed data for inclusion in the meta-analysis.Parents’ assessments favoured LAC in one study (MD -0.57, 95% CI -0.94 to -0.19, n = 17; low-quality evidence), but not in the other (MD -2.80, 95% CI -7.61 to 2.01, n = 51; low-quality evidence), though changes were not large enough to be considered clinically relevant.Regarding social skills, one study reported no clear evidence of a difference in Vineland Adaptive Behavior composite scores (MD 8.20, 95% CI -0.02 to 16.42, n = 51; low-quality evidence), yet results in the socialisation domain favoured LAC (MD 11.30, 95% CI 2.52 to 20.08, n = 51; low-quality evidence).Both studies assessed the safety of the active treatment and recorded no side effects. Neither of the included studies assessed the secondary outcome of caregiver burden. AUTHORS’ CONCLUSIONS: Low-quality evidence from two small trials showed that when compared to placebo, LAC may not improve intellectual functioning or hyperactive behaviour in children with FXS.
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22. Smith MJ, Fleming MF, Wright MA, Losh M, Humm LB, Olsen D, Bell MD. {{Brief Report: Vocational Outcomes for Young Adults with Autism Spectrum Disorders at Six Months After Virtual Reality Job Interview Training}}. {J Autism Dev Disord};2015 (May 19)
Young adults with high-functioning autism spectrum disorder (ASD) have low employment rates and job interviewing presents a critical barrier to employment for them. Results from a prior randomized controlled efficacy trial suggested virtual reality job interview training (VR-JIT) improved interviewing skills among trainees with ASD, but not controls with ASD. We conducted a brief survey with 23 of 26 participants from this study to evaluate their vocational outcomes at 6-month follow-up with a focus on whether or not they attained a competitive position (employment or competitive volunteering). Logistic regression indicated VR-JIT trainees had greater odds of attaining a competitive position than controls (OR 7.82, p < 0.05). Initial evidence suggests VR-JIT is a promising intervention that enhances vocational outcomes among young adults with high-functioning ASD.
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23. Stark Z, Francis D, Gaffney L, Greenberg J, Hills L, Li X, Godler DE, Slater HR. {{Prenatal diagnosis of fragile X syndrome complicated by full mutation retraction}}. {Am J Med Genet A};2015 (May 18)
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24. Turovsky E, Karagiannis A, Abdala AP, Gourine AV. {{Impaired CO sensitivity of astrocytes in a mouse model of Rett syndrome}}. {J Physiol};2015 (May 15)
Rett syndrome, a prototypical neurological disorder caused by loss of function of the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2) gene, is associated with severely disordered breathing pattern and reduced ventilatory CO2 sensitivity. In a mouse model of Rett syndrome (MeCP2 knockout), re-introduction of the MeCP2 gene selectively in astrocytes rescues normal respiratory phenotype. In the present study we determined whether metabolic and/or signalling function of astrocytes is affected by testing the hypothesis that in conditions of MeCP2 deficiency medullary astrocytes are unable to produce/release appropriate amounts of lactate or detect changes in PCO2 /[H+ ], or both. No differences in tonic or hypoxia-induced release of lactate from the ventral surface of the medulla oblongata or cerebral cortex in brain slices of MeCP2-knockout and wild-type mice were found. In brainstem slices of wild-type mice, respiratory acidosis triggered robust elevations in [Ca2+ ]i in astrocytes residing near the ventral surface of the medulla oblongata. The magnitude of CO2 -induced [Ca2+ ]i responses in medullary astrocytes was markedly reduced in conditions of MeCP2 deficiency, whereas [Ca2+ ]i responses to ATP were unaffected. These data suggest that (i) metabolic function of astrocytes in releasing lactate into the extracellular space is not affected by MeCP2 deficiency; (ii) MeCP2 deficiency impairs the ability of medullary astrocytes to sense changes in PCO2 /[H+ ]. Taken together with the evidence of severely blunted ventilatory sensitivity to CO2 in mice with conditional MeCP2 deletion in astroglia, these data support the hypothesis of an important role played by astrocytes in central respiratory CO2 /pH chemosensitivity. This article is protected by copyright. All rights reserved.
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25. Van der Hallen R, Evers K, de-Wit L, Steyaert J, Noens I, Wagemans J. {{Multiple Object Tracking Reveals Object-Based Grouping Interference in Children with ASD}}. {J Autism Dev Disord};2015 (May 16)
The multiple object tracking (MOT) paradigm has proven its value in targeting a number of aspects of visual cognition. This study used MOT to investigate the effect of object-based grouping, both in children with and without autism spectrum disorder (ASD). A modified MOT task was administered to both groups, who had to track and distinguish four targets that moved randomly amongst four distracters, irrespective of the grouping condition. No group difference was revealed between children with and without ASD: both showed adequate MOT abilities and a similar amount of grouping interference. Implications of the current result are considered for previous MOT studies, the developmental trajectory of perceptual grouping, and the idea of heightened sensitivity to task characteristics in ASD.
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26. Van Schalkwyk GI, Lewis AS, Qayyum Z, Koslosky K, Picciotto MR, Volkmar FR. {{Reduction of Aggressive Episodes After Repeated Transdermal Nicotine Administration in a Hospitalized Adolescent with Autism Spectrum Disorder}}. {J Autism Dev Disord};2015 (May 16)
Aggression remains a major cause of morbidity in patients with autism spectrum disorder (ASD). Current pharmacotherapy for aggression is not always effective and is often associated with morbidity. Nicotinic acetylcholinergic neurotransmission may play a prominent role in ASD pathophysiology based on human and animal studies, and preclinical studies show nicotine administration can reduce aggression-related behaviors. Transdermal nicotine has been used to treat agitation in neuropsychiatric conditions with cholinergic dysfunction. Here we report the use of transdermal nicotine as an adjunctive medication to treat aggression in a hospitalized adolescent with ASD. Nicotine patch was recurrently well tolerated, and reduced the need for emergency medication and restraint. These findings suggest further study of transdermal nicotine for aggression comorbid with ASD is warranted.
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27. Wilkinson B, Grepo N, Thompson BL, Kim J, Wang K, Evgrafov OV, Lu W, Knowles JA, Campbell DB. {{The autism-associated gene chromodomain helicase DNA-binding protein 8 (CHD8) regulates noncoding RNAs and autism-related genes}}. {Transl Psychiatry};2015;5:e568.
Chromodomain helicase DNA-binding protein 8 (CHD8) was identified as a leading autism spectrum disorder (ASD) candidate gene by whole-exome sequencing and subsequent targeted-sequencing studies. De novo loss-of-function mutations were identified in 12 individuals with ASD and zero controls, accounting for a highly significant association. Small interfering RNA-mediated knockdown of CHD8 in human neural progenitor cells followed by RNA sequencing revealed that CHD8 insufficiency results in altered expression of 1715 genes, including both protein-coding and noncoding RNAs. Among the 10 most changed transcripts, 4 (40%) were noncoding RNAs. The transcriptional changes among protein-coding genes involved a highly interconnected network of genes that are enriched in neuronal development and in previously identified ASD candidate genes. These results suggest that CHD8 insufficiency may be a central hub in neuronal development and ASD risk.
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28. Wu S, Ding Y, Wu F, Li R, Xie G, Hou J, Mao P. {{Family history of autoimmune diseases is associated with an increased risk of autism in children: A systematic review and meta-analysis}}. {Neurosci Biobehav Rev};2015 (May 15)
BACKGROUND: We conducted a systematic review and meta-analysis to summarize the current evidence on the relationship between family history of autoimmune diseases (ADs) and risk of autism in children, as current evidence suggests inconsistent results. METHODS: We identified relevant studies by searching PubMed, EmBase, and Web of Science databases up to Dec 2014. Risk estimates from individual studies were pooled using random-effects models. Sub-groups analyses were conducted by some study-level factors. Publication bias was assessed by funnel plots, Egger’s regression test and Begg-Mazumdar test. RESULTS: A total of 11 articles were included in the meta-analysis, including 3 cohort studies, 6 case-control studies, and 2 cross-sectional studies. The meta-analysis showed that family history of all ADs combined was associated with a 28% (95% CI: 12-48%) higher risk of autism in children. For some specific ADs, evidence synthesis for risk of autism in children showed a statistically significant association with family history of hypothyroidism (OR=1.64, 95% CI: 1.07-2.50), type 1 diabetes (OR=1.49, 95% CI: 1.23-1.81), rheumatoid arthritis (OR=1.51, 95% CI: 1.19-1.91), and psoriasis (OR=1.59, 95% CI: 1.28-1.97). The results varied in some subgroups. CONCLUSION: An overall increased risk of autism in children with family history of ADs was identified. More mechanistic studies are needed to further explain the association between family history of ADs and increased risk of autism in children.
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29. Yokoyama S, Al Mahmuda N, Munesue T, Hayashi K, Yagi K, Yamagishi M, Higashida H. {{Association Study between the CD157/BST1 Gene and Autism Spectrum Disorders in a Japanese Population}}. {Brain Sci};2015;5(2):188-200.
CD157, also referred to as bone marrow stromal cell antigen-1 (BST-1), is a glycosylphosphatidylinositol-anchored molecule that promotes pre-B-cell growth. Previous studies have reported associations between single-nucleotide polymorphisms (SNPs) of the CD157/BST1 gene with Parkinson’s disease. In an attempt to determine whether SNPs or haplotypes in the CD157/BST1 are associated with other brain disorders, we performed a case-control study including 147 autism spectrum disorder (ASD) patients at Kanazawa University Hospital in Japan and 150 unselected Japanese volunteers by the sequence-specific primer-polymerase chain reaction method combined with fluorescence correlation spectroscopy. Of 93 SNPs examined, two SNPs showed significantly higher allele frequencies in cases with ASDs than in unaffected controls (rs4301112, OR = 6.4, 95% CI = 1.9 to 22, p = 0.0007; and rs28532698, OR = 6.2, 95% CI = 1.8 to 21, p = 0.0012; Fisher’s exact test; p < 0.002 was considered significant after multiple testing correction). In addition, CT genotype in rs10001565 was more frequently observed in the ASD group than in the control group (OR = 15, 95% CI = 2.0 to 117, p = 0.0007; Fisher’s exact test). The present data indicate that genetic variation of the CD157/BST1 gene might confer susceptibility to ASDs.
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30. Yufune S, Satoh Y, Takamatsu I, Ohta H, Kobayashi Y, Takaenoki Y, Pages G, Pouyssegur J, Endo S, Kazama T. {{Transient Blockade of ERK Phosphorylation in the Critical Period Causes Autistic Phenotypes as an Adult in Mice}}. {Sci Rep};2015;5:10252.
The critical period is a distinct time-window during the neonatal stage when animals display elevated sensitivity to certain environmental stimuli, and particular experiences can have profound and long-lasting effects on behaviors. Increasing evidence suggests that disruption of neuronal activity during the critical period contributes to autistic phenotype, although the pathogenic mechanism is largely unknown. Herein we show that extracellular signal-regulated protein kinases (ERKs) play important roles in proper formation of neural circuits during the critical period. Transient blockade of ERKs phosphorylation at postnatal day 6 (P6) by intraperitoneal injection of blood-brain barrier-penetrating MEK inhibitor, alpha-[amino[(4-aminophenyl)thio]methylene]-2-(trifluoromethyl)benzeneacetonitril e (SL327) caused significant increase of apoptosis in the forebrain. Furthermore, this induced long-term deleterious effects on brain functioning later in adulthood, resulting in social deficits, impaired memory and reduced long-term potentiation (LTP). Conversely, blockade of ERK phosphorylation at P14 no longer induced apoptosis, nor behavioral deficits, nor the reduced LTP. Thus, surprisingly, these effects of ERKs are strongly age-dependent, indicating that phosphorylation of ERKs during the critical period is absolutely required for proper development of brain functioning. This study provides novel insight into the mechanistic basis for neurodevelopment disorders: various neurodevelopment disorders might be generally linked to defects in ERKs signaling during the critical period.
